Evidence for a rapid rate of molecular evolution at the hypervariable and immunogenic Mycobacterium tuberculosis PPE38 gene region

McEvoy, Christopher R. E.; Van Helden, Paul D.; Warren, Robin M.; Gey van Pittius, Nicolaas C.

Evidence for a rapid rate of molecular evolution at the hypervariable and immunogenic Mycobacterium tuberculosis PPE38 gene region

dc.contributor.author	McEvoy, Christopher R. E.
dc.contributor.author	Van Helden, Paul D.
dc.contributor.author	Warren, Robin M.
dc.contributor.author	Gey van Pittius, Nicolaas C.
dc.date.accessioned	2010-12-14T10:16:07Z
dc.date.available	2010-12-14T10:16:07Z
dc.date.issued	2009-09
dc.date.updated	2010-10-28T10:36:35Z
dc.description	Includes bibliography
dc.description.abstract	Background: PPE38 (Rv2352c) is a member of the large PPE gene family of Mycobacterium tuberculosis and related mycobacteria. The function of PPE proteins is unknown but evidence suggests that many are cell-surface associated and recognised by the host immune system. Previous studies targeting other PPE gene members suggest that some display high levels of polymorphism and it is thought that this might represent a means of providing antigenic variation. We have analysed the genetic variability of the PPE38 genomic region on a cohort of M. tuberculosis clinical isolates representing all of the major phylogenetic lineages, along with the ancestral M. tuberculosis complex (MTBC) member M. canettii, and supplemented this with analysis of publicly available whole genome sequences representing additional M. tuberculosis clinical isolates, other MTBC members and non tuberculous mycobacteria (NTM). Where possible we have extended this analysis to include the adjacent plcABC and PPE39/40 genomic regions. Results: We show that the ancestral MTBC PPE38 region comprises 2 homologous PPE genes (PPE38 and PPE71), separated by 2 esat-6 (esx)-like genes and that this structure derives from an esx/esx/PPE duplication in the common ancestor of M. tuberculosis and M. marinum. We also demonstrate that this region of the genome is hypervariable due to frequent IS6110 integration, IS6110-associated recombination, and homologous recombination and gene conversion events between PPE38 and PPE71. These mutations result in combinations of gene deletion, gene truncation and gene disruption in the majority of clinical isolates. These mutations were generally found to be IS6110 strain lineage-specific, although examples of additional within-lineage and even within-cluster mutations were observed. Furthermore, we provide evidence that the published M. tuberculosis H37Rv whole genome sequence is inaccurate regarding this region. Conclusion: Our results show that this antigen-encoding region of the M. tuberculosis genome is hypervariable. The observation that numerous different mutations have become fixed within specific lineages demonstrates that this genomic region is undergoing rapid molecular evolution and that further lineage-specific evolutionary expansion and diversification has occurred subsequent to the lineage-defining mutational events. We predict that functional loss of these genes could aid immune evasion. Finally, we also show that the PPE38 region of the published M. tuberculosis H37Rv whole genome sequence is not representative of the ATCC H37Rv reference strain.	en_ZA
dc.description.version	Peer Reviewed
dc.format.extent	21 p. : ill.
dc.identifier.citation	McEvoy, CRE, Van Helden, PD, Warren, RM & Gey van Pittius, NC 2009, Evidence for a rapid rate of molecular evolution at the hypervariable and immunogenic Mycobacterium tuberculosis PPE38 gene region', BMC Evolutionary Biology, 9(1):237.	en_ZA
dc.identifier.issn	1471-2148
dc.identifier.other	http://dx.doi.org/10.1186/1471-2148-9-237
dc.identifier.uri	http://hdl.handle.net/10019.1/5098
dc.language.iso	en_ZA	en_ZA
dc.language.rfc3066	en
dc.publisher	BioMed Central	en_ZA
dc.rights.holder	McEvoy et al.; licensee BioMed Central Ltd.	en_ZA
dc.subject	PPE38 (Rv2352c)	en_ZA
dc.subject	Mycobacterium tuberculosis	en_ZA
dc.title	Evidence for a rapid rate of molecular evolution at the hypervariable and immunogenic Mycobacterium tuberculosis PPE38 gene region	en_ZA
dc.type	Article	en_ZA